1. Field of the Invention
This invention relates in general to peptide-based metal binding ligands, and more particularly to phosphine-containing peptide ligands that provide an asymmetric peptide ligand capable of binding transition metals.
2. Description of Background Art
It has long been known that the phosphine moiety is highly useful as a ligand for a wide variety of catalytically active transition metals. Phosphine metal complexes are known to be used in commercially useful chemical reactions, such as hydroformylation, the hydrogenation of olefins, catalytic allylic alkylation, and the hydrosilation, hydrocyanation, and hydrovinylation of olefins. Phosphine ligands have also been used extensively to bind transition metals for medical uses, such as in the preparation of medical imaging agents.
It has also been a goal of the chemical and pharmaceutical industries to be able to influence the stereospecificity of the product of chemical reactions. In fact, many of the chemical reactions described above have been run using chiral phosphine ligands in an attempt to induce asymmetry in the reaction. Unfortunately, in most cases the enantiomeric excess obtained has been too low for the process to be useful commercially. There has also been an increasing awareness of the advantages of administering only the biologically active enantiomers of pharmaceutical compounds and the use of asymmetric catalysts, using chiral ligands, in the manufacture of such compounds. The technical aspects of these objectives are the subject of extensive research efforts. For example, one can envision using an asymmetric hydroformylation catalyst in the hydroformylation of styrene analogs for the asymmetric synthesis of the class of anti-inflammatory drugs, including Naproxen and analogs thereof. Hydrocarbonylation is a potential route to the production of chiral lactones and lactams, two biologically important functional groups. The chiral phosphine ligands that have been developed to date are, however, typically substrate specific and not suitable for general use. That is, a system that works in an asymmetric fashion with one molecule may not work in the same way with a different molecule.
Typical catalytic phosphine complexes consist of a diphosphine ligand bonded to a chiral hydrocarbon backbone. This places the chirality on one side of the catalytic metal while the actual catalysis must take place at the coordination sites at the opposite side of the metal. This means that in most cases the transfer of chirality from the ligand to the product determining step (the transition state) is not efficient. It is believed that if a chiral ligand could be prepared that is large enough to reach the opposite face of the metal, the ligand would be able to strongly influence the asymmetric environment of the face of the metal where the reaction is taking place and consequently the synthesis of the product. Conventional phosphine-metal chiral ligands having the diphosphine ligand bonded to a chiral hydrocarbon backbone are typically small molecules. To develop a hydrocarbon based chiral ligand that is large enough, or that has a structure capable of affecting the environment at the face of the metal where the reaction takes place, one would encounter great difficulty.
There are a number of types of biological macromolecules that are capable of forming unique, stable three-dimensional structures. It would be desirable to use these structures to control the reactivity of various transition metals. Peptides are large asymmetric molecules that can fold into regular three-dimensional asymmetric secondary structures. It is believed that the highly asymmetric environment of a peptide could be used as a platform for a catalytic metal. Attaching a metal to this large asymmetric ligand could permit the systematic control of the asymmetric environment at the catalytically active face of the metal. If one could provide a means for attaching a metal to a peptide, the stable secondary structure of the peptide would permit the ligand to more readily influence the asymmetric environment at the side of the metal where the reaction takes place. Moreover, peptides often have useful characteristics that could be exploited for various medical applications. For example, a peptide has a distinct solubility, lipophilicity, and bioavailability, and some peptides have selective affinity for particular biological tissues or organs. Moreover, by synthesizing a unique peptide by solid phase peptide synthesis, a peptide having a particular set of characteristics can be designed and synthesized.
In order to utilize the structural characteristics of peptides as a phosphine containing ligand, a method for the incorporation of phosphine into any peptide sequence must be provided. Heretofore, no such method has been developed and no phosphine amino acids or peptides containing phosphine containing amino acids have been reported.